Hypoxia-induced epigenetic reprogramming of cancer stem cells: Linking stemness, metastasis, and therapy resistance

Hypoxia is a defining feature of the solid tumor microenvironment and a central driver of cancer-stem-cell (CSC) biology, yet the epigenetic mechanisms linking oxygen deprivation to stemness, metastasis, and therapy resistance remain fragmented across the literature. This review synthesizes that evidence into a unified mechanistic framework. Beyond the canonical hypoxia-inducible factor (HIF)-1α/HIF-2α switch, hypoxia directly reprograms the epigenome through oxygen-dependent histone demethylases and DNA dioxygenases (TET, JmjC-domain enzymes), establishing chromatin as a parallel, HIF-adjacent oxygen sensor. This crosstalk spans DNA methylation dynamics that gate HIF binding while HIF reciprocally reshapes DNMT/TET expression; histone modifications that redistribute genome-wide and are selectively co-opted at pluripotency loci; and histone lactylation, a metabolically-derived mark we position as an emerging fourth epigenetic pillar - though, as detailed below, its mechanistic demonstration within defined CSC populations remains more preliminary than for the other three layers. We trace how these layers converge on the core pluripotency circuitry (OCT4, SOX2, NANOG, KLF4, MYC), critically examine the limited evidence for a "hypoxic memory" outlasting reoxygenation - currently demonstrated only in bulk tumor and circulating-tumor-cell populations, not defined CSCs - and connect these mechanisms to EMT, circulating-tumor-cell survival, and multi-modal therapy resistance. We distinguish mechanisms demonstrated directly in CSCs from those inferred from general cancer contexts, identifying histone lactylation in CSCs and true post-reoxygenation memory as areas needing further investigation.